Multiple sclerosis (MS) affects 1 in 1000 individuals in the US and is characterized by progressive sensory, motor and cognitive impairments. These functional deficits are linked to inflammatory attacks on myelin, oligodendrocytes, and axons. Therapeutic strategies that promote remyelination, protect against inflammation, and protect axons have the potential to prevent and even improve functional declines in MS patients. One therapeutic approach is to use neural stem cells (NSCs), which are able to rescue endangered host neurons and glial cells by providing trophic support, detoxifying the microenvironment, mobilizing endogenous progenitors, triggering self-repair mechanisms, exerting anti-inflammatory and anti-scarring actions, and promoting angiogenesis. Each of these effects has the potential to improve outcomes in MS patients. Intravenous administration of NSCs is an alternative to direct injections into the CNS. This approach is feasible because systemically administered NSCs can circumvent the blood-brain barrier (BBB) and localize to a site of intracranial pathology. However, one limitation of this approach is that NSCs are extremely inefficient (<5% cells) at homing, even to an injured site in the brain. We have found that the molecules mediating homing in NSCs are defective, which contributes to the poor efficiency of NSC homing. Our preliminary in vitro data show that our proprietary technology, ASC-101, corrects this natural deficiency and improves interactions of NSCs under conditions of physiological shear stress. This Phase I SBIR grant submission is designed to generate a proof-of-principle that ex vivo correction of NSC homing molecules will improve their homing to MS lesions in a mouse model of MS. In Aim 1 we will complete the production of research-grade ASC-101 for use in experiments under this grant. In Aim 2, ASC- 101-treated NSCs will be intravenously injected in experimental autoimmune encephalomyelitis (EAE) mice and we will evaluate their migration to the lesions, differentiation and overall efficacy. EAE is a widely accepted and utilized animal model of MS. If successful, this project will provide the basis for further testing ASC-101 technology in additional animal models of MS using NSCs.